Aminothiol compound

ABSTRACT

The present invention discloses an aminothiol compound having a general formula I wherein R 1 -R 5  are substitutable ligands. Such compound can perform as a superior catalyst in an asymmetric addition reaction of organic metal compounds and aldehyde. According to the present invention, the aminothiol compound is needed only less than 0.02% based on main reactants to obtain enantioselectivity higher than 98% enantiomeric excess, whereby the asymmetric reactions can become very economic.

CROSS-REFERENCE TO RELATED APPLICATION

This is a CIP application of U.S. patent application Ser. No. 10/039,557filed on Jan. 8, 2002, and for which priority is claimed under 35U.S.C.sctn.120.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates aminothiol compounds which perform assuperior catalysts in the asymmetric addition reactions of organic zincand aldehyde.

2. Description of the Related Technology

For preparing secondary alcohols, one of the most important methods isto react organic zinc with aldehyde in addition reactions. In order toaccelerate this reaction, chiral aminoalcohols are usually added asligands to combine with organic zinc. Such chiral aminoalcohol create anasymmetric reaction environment, so that one of the produced chiralsecondary alcohols is produced more than its stereoisomer, i.e., theasymmetric addition reactions. Apparently, the crux of obtaining a highchemical yield as well as enantioselectivity in the above reactions isto select proper chiral compounds which can provide excellent asymmetricenvironment for catalytical process.

Though many chiral compounds used in the addition reactions regardingorganic zinc and aldehyde can achieve good enantioselectivity, however,these compounds have to be added at an amount at least 1% of the mainreactants, and usually around 20%. Additionally, the enantioselectivityalways decays with decreasing amount of the chiral ligands used. Ingeneral, the enantioselectivity is reduced below 90% enantiomeric excess(e.e.) when the chiral ligands are descended under 5%, so that most ofabove reactions are not good enough for industrial usage.

Aminoalcohols with optical activity, such as N,N-dibutylnorephe-edine,are frequently applied to accelerating the asymmetric addition reactionsof organic zinc and aldehyde as chiral ligand catalysts. By addingaminoalcohols, enantioselectivity of the above reactions can be reachedas high as 99% e.e., but an amount 10-20% of chiral aminoalcohols isneed. Therefore, it's an important issue how to reduce the necessaryamount of the chiral ligands used in the catalysis, so that it can be aneconomically efficient process

SUMMARY OF THE INVENTION

The object of the present invention is to provide aminothiol compoundswith two chiral centers, which can increase enantioselectivity ofasymmetric addition of organic zinc and aldehyde.

In order to achieve the above object, the present invention discloses anaminothiol compound having a general formula I;

wherein R¹-R⁵ are substitutable ligands.

According to the present invention, the aminothiol compounds can performas superior catalysts in asymmetric addition reactions wherein organiczinc and aldehyde are involved. In such reactions, though the catalystsare added only 0.1% or even 0.02%, enantioselectivity higher than 98%e.e. can always be obtained. Such catalyses are economically useful forindustries.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, aminothiol compounds have a general formula I,

wherein R¹ is aryl or alkyl of C1-C9;

-   -   R² is aryl or alkyl of C1-C9;    -   R³ is aryl or alkyl of C1-C9;    -   R⁴ is aryl or alkyl of C1-C9; or    -   R³, R⁴ and N form a three-to-eight-membered heterocycle;    -   with the proviso that R³, R⁴ and N form pyrrolidinyl or        morpholinyl as R¹ and R² are both phenyl; and    -   R⁵ is H or alkyl of C1-C6.        [Preparation Mode]

In general, the aminothiol compounds can be prepared through proceduresshown in Scheme A.

Scheme A includes steps of: (a) reacting amino-alcohol withbromo-compound and carbonate of alkaline metal to form the specificligand of R³, R⁴ and N; (b) replacing —OH with —SAc by adding MeSO₂Cland NEt₃ (c) adding LiAlH₄ to form —SH.

The following EXAMPLEs indicate procedures for preparing representativeaminothiol compounds of the present invention. Table 1 lists codes ofdifferent ligands shown in the compound of formula (I), so that theaminothiol compounds of the present invention can be simply representedwith combinations of such codes.

TABLE 1 R¹ R² N-R³-R⁴ R⁵ code ligand code ligand code ligand code ligand2 methyl b methyl 2 Bu^(n) c H (n-butyl) 3 Bu^(n) c Bu^(n) 3 Bn(n-butyl) (n-butyl) (benzyl) 4 i-butyl f i-propyl 4 pyrro- lidinyl 5 Bng Ph 5 piperidyl (benzyl) (phenyl) 6 i-propyl 6 morpho- linyl 7 Ph(phenyl)

For example, compound (2b4c) is an aminothiol compound of the presentinvention, wherein R¹ is methyl; R² is methyl; N, R³ and R⁴ form afive-membered heteorocycle, pyrrolidinyl; and R⁵ is H. As for the middleproduct obtained in step (a), the last code “a” represents the alcoholligand, —OH.

EXAMPLES 1 AND 2 Preparation of (2R,3S)-4-Methyl-3-(1-pyrrolidinyl)pentane-2-thiol (6b4c) and(3R,4S)-2-Methyl-4-(1-pyrrolidinyl)pentane-3-thiol (2f4c) Step (a):Preparing (2R,3S)-4-Methyl-3-(1-pyrrolidinyl)pentan-2-ol (6b4a)

To a three-necked flask, (2R,3S)-3-amino-4-methylpentan-2-ol (0.585 g,5.0 mmol), Na₂CO₃ (1.16 g, 11.0 mmol) and CH₃CN (20 mL) are added underthe nitrogen system and then heated with refluxing. Next, Br₂C₄H₈ (1.295g, 6.0 mmol) is injected into the solution. After complete reaction for12 hours, H₂O (20 mL) is added to terminate the reaction. The product isrepeatedly extracted with EtOAc (20 mL), wherein the organic phase isdehydrated with Na₂SO₄. A coarse product is obtained after filtrationand concentration. Column chromatography (Silica gel 50 g, eluent isn-Hexane:EtOAc=1:1) is used to purify the coarse product and aslightly-yellow liquid (0.85 g) is obtained. The yield is 85% and theother analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.87 (d, J=6.4 Hz, 3H, CH(CH₃)₂), 0.96 (d, J=6.4 Hz, 3H,        CH(CH₃)₂), 1.05 (d, J=6.4 Hz, 3H, CHOHCH₃), 1.72-1.79 (m, 4H,        —(CH₂)₂—), 1.82-2.00 (m, 1H, CH(CH₃)₂), 2.48 (dd, J₁=4.8 Hz,        J₂=10.0 Hz, 1H, NCH), 2.80-2.92 (m, 4H, NCH₂—), 3.70-3.80 (m,        1H, CHOH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 18.59 (CHOHCH₃), 19.80 (CH(CH₃)₂), 21.38 (CH(CH₃)₂), 23.93        (—CH₂—) 27.30 (CH(CH₃)₂), 50.91 (NCH₂—), 65.64 (NCH), 69.50        (CHOH)        Element analysis: C₁₀H₂₁NO    -   theoretical: C, 70.12; H, 12.36; N, 8.18    -   experimental: C, 71.16; H, 12.28; N, 8.14        High-resolution MS (70 eV) m/e theoretical: 171.1623    -   experimental: 172.1699        [α]²⁵ _(D)=+42.1 (c=1.45, CDCl₃)

Step (b): Preparing(2R,3S)-4-Methyl-3-(1-pyrrolidinyl)-2-thioacetylpentane (6b4b)

and (3R,4S)-2-Methyl-4-(1-pyrrolidinyl)-3-thioacetylpentane (2f4b)

To a three-necked flask, compound (6b4a) (0.855 g, 5.0 mmol), CH₂Cl₂ (20mL) and NEt₃ (1.01 g, 10.0 mmol) are added under nitrogen system. Next,MeSO₂Cl (0.69 g, 6.0 mmol, dissolved in 20 mL CH₂Cl₂) is addeddropwisely at 0° C. After complete reaction for 2 hours, a coarseproduct is obtained through repeated depressing concentration and addingbenzene therein. The coarse product is then added into benzene (20 mL)with refluxing, and MeCOSH (0.46 g, 6.0 mmol) and NEt₃ (1.01 g, 10.0mmol) dissolved in 20 mL benzene are injected into the above solutionunder the nitrogen system. After 12 hours, H₂O (20 mL) is added toterminate the reaction. The product is repeatedly extracted with EtOAc(20 mL), wherein the organic phase is dehydrated with Na₂SO₄. A coarseproduct is obtained after filtration and concentration. Columnchromatography (Silica gel 70 g, eluent is n-Hexane:NEt₃=100:1) is usedto purify the coarse product and two orange liquids, compound (6b4b)(0.229 g) and compound (2f4b) (0.458 g), are obtained. The yields ofcompound (6b4b) and compound (2f4b) are 20% and 40%, respectively. Theother analysis for compound (6b4b) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.92 (d, J=7.2 Hz, 3H, CH(CH₃)₂), 0.94 (d, J=7.2 Hz, 3H,        CH(CH₃)₂), 1.27 (d, J=6.8 Hz, 3H, SCHCH₃), 1.66-1.73 (m, 4H,        —(CH₂)₂—), 1.90-2.05 (m, 1H, CH(CH₃)₂), 2.27 (s, 3H, SCOCH₃),        2.41 (dd, J₁=3.2 Hz, J₂=8.0 Hz, 1H, NCH), 2.67-2.74 (m, 2H,        NCH₂—), 2.75-2.81 (m, 2H, NCH₂—), 3.86-4.05 (m, 1H, SCH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 18.38 (SCHCH₃) 20.37 (CH(CH₃)₂), 21.18 (CH(CH₃)₂), 24.20        (—CH₂—), 29.40 (CH(CH₃)₂), 30.66 (SCOCH₃), 43.29 (NCH) 51.06        (NCH₂—), 69.61 (SCHCH₃), 196.77 (SCOCH₃)        Element analysis C₁₂H₂₃NOS    -   theoretical: C, 62.83; H, 10.11; N, 6.11    -   experimental: C, 62.90; H, 10.10; N, 6.02        High-resolution MS (70 eV) m/e theoretical: 229.1500    -   experimental: 229.1523        [α]25D=+48.1° (c=1.05, CDCl₃)        The other analysis for compound (2f4b) includes:        ¹H NMR (400 MHz, CDCl₃)    -   δ 0.91 (d, J=6.8 Hz, 3H, CH(CH₃)₂), 0.96 (d, J=7.2 Hz, 3H,        CH(CH₃)₂), 1.03 (d, J=6.8 Hz, 3H, NCHCH₃), 1.68-1.73 (m, 4H,        —(CH₂)₂—), 1.86-2.11 (m, 1H, CH(CH₃)₂), 2.33 (s, 3H, SCOCH₃),        2.42-2.64 (m, 4H, NCH₂—), 2.42-2.64 (m, 1H, NCH), 3.60 (dd,        J₁=4.8 Hz, J₂=8.0 Hz, 1H, SCH),        ¹³C NMR (100 MHz, CDCl₃)    -   δ 13.78 (NCHCH₃) 19.81 (CH(CH₃)₂), 20.78 (CH(CH₃)₂), 23.26        (—CH₂—), 30.25 (CH(CH₃)₂), 30.72 (SCOCH₃), 50.64 (NCH₂—), 54.84        (NCH), 58.89 (SCHCH₃), 195.56 (SCOCH₃)        Element analysis C₁₂H₂₃NOS    -   theoretical: C, 62.83; H, 10.11; N, 6.11    -   experimental: C, 62.56; H, 10.25; N, 5.97        High-resolution MS (70 eV) m/e theoretical: 299.1500    -   experimental: 299.1508        [α]25D=+41.7° (c=0.99, CDCl₃)

Step (c): Preparing (2R,3S)-4-Methyl-3-(1-pyrrolidinyl)pentane-2-thiol(6b4c)

and (3R,4S)-2-Methyl-4-(1-pyrrolidinyl)pentane-3-thiol (2f4c)

To a three-necked flask, LAH (LiAlH₄, 0.076 g, 2.0 mmol) and ether (10mL) are added under nitrogen system. Next, compound (6b4b) (0.229 g, 1.0mmol) or compound (2f4b) (0.229 g, 1.0 mmol) dissolved in 10 mL ether isslowly added into the flask within 30 min at 0° C. After reaction for 1hour, 15% NaOH is added to the flask until a white solid is presentcomplete. The solid is filtered and repeatedly washed with a solvent.The filtrate is then concentrated to obtain a coarse product. Columnchromatography (Silica gel 40 g, eluent is n-Hexane:NEt₃=100:1) is usedto purify the coarse product and two orange liquids, compound (6b4c)(0.15 g) and compound (2f4c) (0.15 g), are obtained. The yields ofcompound (6b4c) and compound (2f4b) are 80% and 80%, respectively. Theother analysis for compound (6b4c) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.88 (d, J=6.8 Hz, 3H, CH(CH₃)₂), 0.93 (d, J=6.4 Hz, 3H,        CH(CH₃)₂), 1.35 (d, J=6.8 Hz, 3H, CHSHCH₃), 1.65-1.73 (m, 4H,        —(CH₂)₂—), 1.98-2.10 (m, 1H, CH(CH₃)₂), 2.55 (dd, J₁=3.6 Hz,        J₂=7.2 Hz, 1H, NCH), 2.70-2.75 (m, 2H, NCH₂—), 2.76-2.82 (m, 2H,        NCH₂—), 3.03-3.20 (m, 1H, CHOH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 20.75 (CH(CH₃)₂), 21.24 (CHSHCH₃), 22.26 (CH(CH₃)₂), 24.49        (—CH₂—) 29.17 (CH(CH₃)₂), 38.44 (NCH), 51.18 (NCH₂—), 70.87        (SCH)        Element analysis C₁₀H₂₁NS    -   theoretical: C, 64.11; H, 11.30; N, 7.48    -   experimental: C, 64.35; H, 11.12; N, 7.65        High-resolution MS (70 eV) m/e theoretical: 187.1395    -   experimental: 187.1366        [α]25D=+17.4° (c=0.83, CDCl₃)        The other analysis for compound (2f4c) includes:        ¹H NMR (400 MHz, CDCl₃)    -   δ 0.92 (d, J=6.8 Hz, 3H, CH(CH₃)₂), 1.01 (d, J=6.4 Hz, 3H,        CH(CH₃)₂), 1.04 (d, J=6.4 Hz, 3H, NCHCH₃), 1.69-1.75 (m, 4H,        —(CH₂)₂—), 1.69-1.75 (m, 1H, CH(CH₃)₂), 2.35-2.41 (m, 1H, NCH),        2.43-2.49 (m, 2H, NCH₂—), 2.52-2.58 (m, 2H, NCH₂—), 2.84 (dd,        J₁=4.0 Hz, J₂=9.6 Hz, 1H, SHCH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 12.08 (NCHCH₃), 20.47 (CH(CH₃)₂), 21.71 (CH(CH₃)₂), 23.27        (—CH₂—) 31.24 (CH(CH₃)₂), 50.95 (NCH₂—), 52.17 (NCH), 60.54        (SCH)        Element analysis C₁₀H₂₁NS    -   theoretical: C, 64.11; H, 11.30; N, 7.48    -   experimental: C, 63.98; H, 11.25; N, 7.45        High-resolution MS (70 eV) m/e theoretical: 187.1395    -   experimental: 187.1386        [α]25D=+23.7° (c=1.51, CDCl₃)

EXAMPLES 3 AND 4 Preparation of (3S,4R)-2-Methyl-3-(1-pyrrolidinyl)octane-4-thiol (6c4c) and(3R,4S)-2-Methyl-4-(1-pyrrolidinyl)octane-3-thiol (3f4c) Step (a):Preparing (3S,4R)-2-Methyl-3-(1-pyrrolidinyl)octan-4-ol (6c4a)

Repeat Step (a) of EXAMPLE 1, but (2R,3S)-3-amino-4-methyl pentan-2-olis replaced with (3S,4R)-3-amino-2-methyloctan-4-ol. The analysis forcompound

(6c4a) includes:

¹H NMR(400 MHz, CDCl₃)

-   -   δ 0.77-0.92 (m, 3H, (CH₂)₃CH₃), 0.77-0.92 (m, 6H, CH(CH₃)₂),        1.06-1.62 (m, 6H, (CH₂)₃CH₃), 1.62-1.81 (m, 4H, —(CH₂)₂—),        1.89-2.05 (m, 1H, CH(CH₃)₂), 2.47 (dd, J₁=4.8 Hz, J₂=9.6 Hz, 1H,        NCH), 2.74-2.86 (m, 4H, NCH₂—), 3.45-3.52 (m, 1H, CHOH),        ¹³C NMR(100 MHz, CDCl₃)    -   δ 13.99 (CH₂CH₂CH₂CH₃), 20.20 (CH(CH₃)₂), 21.81 (CH(CH₃)₂),        22.66 (CH₂CH₂CH₂CH₃), 24.23 (—CH₂—), 27.48 (CH(CH₃)₂), 29.23        (CH₂CH₂CH₂CH₃), 32.21 (CH₂CH₂CH₂CH₃), 50.85 (NCH₂—), 69.11        (NCH), 70.58 (CHOH)        Element analysis C₁₃H₂₇NO    -   theoretical: C, 73.18; H, 12.76; N, 6.56    -   experimental: C, 73.20; H, 12.63; N, 6.51        High-resolution MS (70 eV) m/e theoretical: 213.2093    -   experimental: 214.2165        [α]25D=+53.3° (c=1.03, CDCl₃)

Step (b): Preparing(3S,4R)-2-Methyl-3-(1-pyrrolidinyl)-4-thioacetyloctane (6c4b)

and (3R,4S)-2-Methyl-4-(1-pyrrolidinyl)-3-thioacetyloctane (3f4b)

Repeat Step (b) of EXAMPLE 1, but replace compound (6b4a) with compounds(6c4a) or (3f4a). Analysis for product (6c4b) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.85 (t, J=7.2 Hz, 3H, (CH₂)₃CH₃), 0.86 (d, J=5.6 Hz, 3H,        CH(CH₃)₂), 0.95 (d, J=5.6 Hz, 3H, CH(CH₃)₂), 1.20-1.50 (m, 6H,        (CH₂)₃CH₃), 1.64-1.72 (m, 4H, —(CH₂)₂—), 1.85-2.12 (m, 1H,        CH(CH₃)₂), 2.28 (s, 3H, SCOCH₃), 2.43 (dd, J₁=2.8 Hz, J₂=8.0 Hz,        1H, NCH), 2.58-2.66 (m, 2H, NCH₂—), 2.68-2.77 (m, 2H, NCH₂—),        3.80-3.88 (m, 1H, SCH),        ¹³C NMR (100 MHz, CDCl₃)    -   δ 14.00 (CH₂CH₂CH₂CH₃), 20.50 (CH(CH₃)₂), 21.19 (CH(CH₃)₂),        22.56 (CH₂CH₂CH₂CH₃), 23.99 (—CH₂—), 29.54 (CH(CH₃)₂), 29.58        (CH₂CH₂CH₂CH₃), 30.53 (SCOCH₃), 32.16 (CH₂CH₂CH₂CH₃), 47.53        (NCH), 50.79 (NCH₂—), 70.19 (SCH), 196.26 (SCOCH₃)        Element analysis C₁₅H₂₉NOS    -   theoretical: C, 66.37; H, 10.77; N, 5.16    -   experimental: C, 66.14; H, 10.85; N, 5.22        High-resolution MS (70 eV) m/e theoretical: 271.1970    -   experimental: 271.1971        [α]25D=+39.6° (c=1.03, CDCl₃)        Analysis for product (3f4b) includes:        ¹H NMR(400 MHz, CDCl₃)    -   δ 0.82-0.90 (m, 3H, (CH₂)₃CH₃), 0.82-0.90 (m, 3H, CH(CH₃)₂),        0.93 (d, J=6.4 Hz, 3H, CH(CH₃)₂), 1.20-1.60 (m, 6H, (CH₂)₃CH₃),        1.65-1.73 (m, 4H, —(CH₂)₂—), 1.91-2.05 (m, 1H, CH(CH₃)₂), 2.31        (s, 3H, SCOCH₃), 2.50-2.63 (m, 4H, NCH₂—), 2.50-2.63 (m, 1H,        NCH), 3.63 (t, J=6.0 Hz, 1H, SCH),        ¹³C NMR (100 MHz, CDCl₃)    -   δ 13.91 (CH₂CH₂CH₂CH₃), 19.07 (CH(CH₃)₂), 20.83 (CH(CH₃)₂),        22.98 (CH₂CH₂CH₂ CH₃), 23.56 (—CH₂—), 30.26 (CH(CH₃)₂), 30.49        (CH₂CH₂CH₂CH₃), 30.70 (SCOCH₃), 30.79 (CH₂CH₂CH₂CH₃), 49.33        (NCH₂—), 53.70 (NCH), 61.89 (SCH), 195.68 (SCOCH₃)        Element analysis C₁₅H₂₉NOS    -   theoretical: C, 66.37; H, 10.77; N, 5.16    -   experimental: C, 66.23; H, 10.71; N, 5.02        High-resolution MS (70 eV) m/e theoretical: 271.1970    -   experimental: 271.1991        [α]25D=+48.2° (c=1.24, CDCl₃)

Step (c): Preparing (3S,4R)-2-Methyl-3-(1-pyrrolidinyl)octane-4-thiol(6c4c)

and (3R,4S)-2-Methyl-4-(1-pyrrolidinyl) octane-3-thiol (3f4c)

Repeat Step (c) of EXAMPLE 1, but replace compound (6b4b) with compounds(6c4b) or (3f4b). Analysis for product (6c4c) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.84-1.00 (m, 6H, CH(CH₃)₂), 0.84-1.00 (m, 3H, (CH₂)₃CH₃),        1.16-1.35 (m, 4H, CH₂(CH₂)₂CH₃), 1.48-1.78 (m, 2H,        CH₂(CH₂)₂CH₃), 1.48-1.78 (m, 4H, —(CH₂)₂—), 2.00-2.13 (m, 1H,        CH(CH₃)₂), 2.43 (dd, J₁=3.6 Hz, J₂=8.4 Hz, 1H, NCH), 2.71-2.93        (m, 4H, NCH₂—), 2.71-2.963 (m, 1H, SHCH),        ¹³C NMR (100 MHz, CDCl₃)    -   δ 14.07 (CH₂CH₂CH₂CH₃), 20.88 (CH(CH₃)₂), 21.39 (CH(CH₃)₂),        22.49 (CH₂CH₂CH₂CH₃), 24.39 (—CH₂—), 28.90 (CH(CH₃)₂), 30.54        (CH₂CH₂CH₂CH₃), 34.56 (CH₂CH₂CH₂CH₃), 44.95 (NCH), 51.01        (NCH₂—), 70.85 (CHSH)        Element analysis C₁₃H₂₇NS    -   theoretical: C, 68.06; H, 11.86; N, 6.11    -   experimental: C, 68.21; H, 11.55; N, 6.35        High-resolution MS (70 eV) m/e theoretical: 229.1864    -   experimental: 229.1857        [α]25D=+54.3° (c=10.01, CDCl₃)        Analysis for product (3f4c) includes:        ¹H NMR (400 MHz, CDCl₃)    -   δ 0.86-1.00 (m, 3H, (CH₂)₃CH₃), 0.86-1.00 (m, 6H, CH(CH₃)₂),        1.23-1.50 (m, 4H, CH₂(CH₂)₂CH₃), 1.52-1.73 (m, 2H,        CH₂(CH₂)₂CH₃), 1.52-1.73 (m, 4H, —(CH₂)₂—), 1.75-1.92 (m, 1H,        CH(CH₃)₂), 2.33 (dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H, NCH), 2.47-2.62        (m, 4H, NCH₂—), 2.85 (dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H, SHCH),        ¹³C NMR (100 MHz, CDCl₃)    -   δ 13.92 (CH₂CH₂CH₂CH₃), 20.13 (CH(CH₃)₂), 21.23 (CH(CH₃)₂),        23.21 (CH₂CH₂CH₂CH₃), 23.43 (—CH₂—), 29.30 (CH₂CH₂CH₂CH₃), 30.65        (CH(CH₃)₂), 31.42 (CH₂CH₂CH₂CH₃), 50.24 (NCH₂—), 51.99 (NCH),        64.56 (CHSH)        Element analysis C₁₃H₂₇NS    -   theoretical: C, 68.06; H, 11.86; N, 6.11    -   experimental: C, 68.21; H, 11.56; N, 6.01        High-resolution MS (70 eV) m/e theoretical: 229.1864    -   experimental: 229.1857        [α]25D=+38.8° (c=0.99, CDCl₃)

EXAMPLE 5 Preparation of(3R,4S)-2,5-Dimethyl-4-(1-pyrrolidinyl)hexane-3-thiol (6f4c) Step (a):Preparing (3R,4S)-2,5-Dimethyl-4-(1-pyrrolidinyl)hexan-3-ol (6f4a)

Repeat Step (a) of EXAMPLE 1, but replace(2R,3S)-3-amino-4-methylpentan-2-ol with(3R,4S)-4-amino-2,5-dimethylhexan-3-ol. Analysis for compound (6f4a)includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.83 (d, J=6.8 Hz, 3H, NCHCH(CH₃)₂), 0.97 (d, J=6.8 Hz, 3H,        NCHCH(CH₃)₂), 1.02 (d, J=1.2 Hz, 3H, CHOHCH(CH₃)₂), 1.04 (d,        J=1.2 Hz, 3H, CHOHCH(CH₃)₂), 1.63-1.73 (m, 4H, —(CH₂)₂—),        1.74-1.83 (m, 1H, NCHCH(CH₃)₂), 2.05-2.12 (m, 1H, CHOHCH(CH₃)₂),        2.21 (dd, J₁=3.2 Hz, J₂=4.0 Hz, 1H, NCH), 2.55-2.63 (m, 2H,        NCH₂—), 2.65-2.72 (m, 2H, NCH₂—), 3.41 (dd, J₁=4.4 Hz, J₂=9.2        Hz, 1H, CHOH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 19.20 (NCHCH(CH₃)₂), 19.30 (NCHCH(CH₃)₂), 19.62        (CHOHCH(CH₃)₂), 22.68 (CHOHCH(CH₃)₂), 23.40 (—CH₂—) 26.99        (NCHCH(CH₃)₂), 30.59 (CHOHCH(CH₃)₂), 51.59 (NCH₂—), 68.34 (NCH),        77.60 (CHOH)        Element analysis C₁₂H₂₅NO    -   theoretical: C, 72.31; H, 12.64; N, 7.03    -   experimental: C, 72.18; H, 12.73; N, 6.89        High-resolution MS (70 eV) m/e theoretical: 199.1936    -   experimental: 200.2011        [α]25D=+45.7° (c=1.21, CDCl₃)

Step (b): Preparing(3R,4S)-2,5-Dimethyl-4-(1-pyrrolidinyl)-3-thioacetylhexane (6f4b)

Repeat Step (b) of EXAMPLE 1, but replace compound (6b4a) with compound(6f4a). Analysis for product (6f4b) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.88 (d, J=6.8 Hz, 3H, NCHCH(CH₃)₂), 0.90-0.98 (m, 3H,        NCHCH(CH₃)₂), 0.90-0.98 (m, 6H, SCHCH(CH₃)₂), 1.66-1.71 (m, 4H,        —(CH₂)₂—), 1.88-2.00 (m, 1H, NCHCH(CH₃)₂), 2.01-2.12 (m, 1H,        SCHCH(CH₃)₂), 2.34 (s, 3H, SCOCH₃), 2.62-2.70 (m, 2H, NCH₂—),        2.71-2.77 (m, 2H, NCH₂—), 2.62-2.77 (m, 1H, NCH), 3.79 (dd,        J₁=5.2 Hz, J₂=6.4 Hz, 1H, SCH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 18.62 (NCHCH(CH₃)₂), 19.99 (NCHCH(CH₃)₂), 21.10 (SCHCH(CH₃)₂),        21.59 (SCHCH(CH₃)₂), 24.01 (—CH₂—) 30.44 (NCHCH(CH₃)₂), 30.54        (SCHCH(CH₃)₂), 30.70 (SCOCH₃), 49.24 (NCH₂—), 50.80 (NCH), 64.73        (SCH), 195.37 (SCOCH₃)        Element analysis C₁₄H₂₇NOS    -   theoretical: C, 65.32; H, 10.57; N, 5.44    -   experimental: C, 65.20; H, 10.81; N, 5.14        High-resolution MS (70 eV) m/e theoretical: 257.1813    -   experimental: 257.1859        [α]25D=+53.9° (c=1.23, CDCl₃)

Step (c): Preparing(3R,4S)-2,5-Dimethyl-4-(1-pyrrolidinyl)hexane-3-thiol (6f4c)

Repeat Step (c) of EXAMPLE 1, but replace compound (6b4b) with compound(6f4b). Analysis for product (6f4c) includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.89 (d, J=6.4 Hz, 3H, NCHCH(CH₃)₂), 0.92-1.06 (m, 3H,        NCHCH(CH₃)₂), 0.92-1.06 (m, 6H, SHCHCH(CH₃)₂), 1.62-1.72 (m, 4H,        —(CH₂)₂—), 1.89-1.95 (m, 1H, NCHCH(CH₃)₂), 2.13-2.25 (m, 1H,        SHCHCH(CH₃)₂), 2.52 (dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H, NCH),        2.64-2.73 (m, 4H, NCH₂—), 2.92 (dd, J₁=4.4 Hz, J₂=7.6 Hz, 1H,        CHSH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 17.63 (NCHCH(CH₃)₂), 19.56 (NCHCH(CH₃)₂), 21.57        (CHSHCH(CH₃)₂), 21.79 (CHSHCH(CH₃)₂), 24.14 (—CH₂—) 29.40        (NCHCH(CH₃)₂), 29.69 (CHSHCH(CH₃)₂), 48.77 (NCH), 50.03 (NCH₂—),        66.19 (CHSH)        Element analysis C₁₂H₂₅NS    -   theoretical: C, 66.91; H, 11.70; N, 6.50    -   experimental: C, 66.38; H, 10.91; N, 6.28        High-resolution MS (70 eV) m/e theoretical: 215.1708    -   experimental: 215.1712        [α]25D=+13.7° (c=0.99, CDCl₃)

EXAMPLE 6 Preparation of(1R,2S)-3-Methyl-1-phenyl-2-(1-pyrrolidinyl)butane-1-thiol (6g4c) Step(a): Preparing (1R,2S)-3-Methyl-1-phenyl-2-(1-pyrrolidinyl)butan-1-ol(6g4a)

Repeat Step (a) of EXAMPLE 1, but replace(2R,3S)-3-amino-4-methylpentan-2-ol with(1R,2S)-2-amino-3-methyl-1-phenylbutan-1-ol, and replace Na₂CO₃ (1.16 g,11.0 mmol) with K₂CO₃ (1.52 g, 11.0 mmol). Column chromatography (Silicagel, eluent is n-Hexane:EtOAc=10:1) is used to purify the coarse productand a slightly-yellow liquid (1.00 g) is obtained. The yield is 86% andthe other analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.80 (d, J=6.8 Hz, 3H, CH(CH₃)₂), 0.96 (d, J=6.8 Hz, 3H,        CH(CH₃)₂), 1.62-1.70 (m, 4H, —(CH₂)₂—), 1.72-1.82 (m, 1H,        CH(CH₃)₂), 2.54 (dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H, NCH), 2.57-2.64        (m, 2H, NCH₂—), 2.68-2.74 (m, 2H, NCH₂—), 4.92 (d, J=4.0 Hz, 1H,        CHOH), 7.14-7.34 (m, 5H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 20.28 (CH(CH₃)₂), 21.81 (CH(CH₃)₂), 23.78 (—CH₂—), 27.88        (CH(CH₃)₂), 51.47 (NCH₂—), 72.29 (NCH), 72.51 (CHOH), 126.08,        126.62, 127.79, 142.88 (Ph)        Element analysis C₁₅H₂₃NO    -   theoretical: C, 77.21; H, 9.93; N, 6.00    -   experimental: C, 77.11; H, 9.73; N, 6.23        High-resolution MS (70 eV) m/e theoretical: 233.1780    -   experimental: 234.1865        [α]25D=−41.3° (c=1.38, CDCl₃)

Step (b): Preparing(1R,2S)-3-Methyl-1-phenyl-2-(1-pyrrolidinyl)-1-thioacetyl butane (6g4b)

Repeat Step (b) of EXAMPLE 1, but replace compound (6b4a) with compound(6g4a). Column chromatography (Silica gel, eluent isn-Hexane:NEt₃=100:1) is used to purify the coarse product and aslightly-yellow liquid (1.09 g) is obtained. The yield is 75% and theother analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.90 (d, J=6.8 Hz, 3H, CH(CH₃)₂), 0.99 (d, J=6.4 Hz, 3H,        CH(CH₃)₂), 1.45-1.55 (m, 4H, —(CH₂)₂—), 1.92-2.04 (m, 1H,        CH(CH₃)₂), 2.26 (s, 3H, SCOCH₃), 2.60-2.69 (m, 4H, NCH₂—), 2.97        (t, J=6.4 Hz, 1H, NCH), 4.99 (d, J=6.4 Hz, 1H, SCH), 7.14-7.41        (m, 5H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 19.82 (CH(CH₃)₂), 21.62 (CH(CH₃)₂), 24.31 (—CH₂—), 30.57        (CH(CH₃)₂), 30.59 (SCOCH₃), 49.69 (NCH), 50.42 (NCH₂—), 69.33        (SCH), 126.73, 127.86, 128.70, 141.80 (Ph), 194.60 (SCOCH₃)        Element analysis C₁₇H₂₅NOS    -   theoretical: C, 70.06; H, 8.65; N, 4.81    -   experimental: C, 69.68; H, 8.80; N, 4.63        High-resolution MS (70 eV) m/e theoretical: 291.1657    -   experimental: 291.1661        [α]25D=−240.8° (c=1.02, CDCl₃)

Step (c): Preparing (1R,2S)-3-Methyl-1-phenyl-2-(1-pyrrolidinyl)butane-1-thiol (6g4c)

Repeat Step (c) of EXAMPLE 1, but replace compound (6b4b) with compound(6g4b). A slightly-yellow liquid (0.401 g) is obtained through pumpingconcentration. The yield is 85% and other analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.95 (d, J=7.2 Hz, 3H, CH(CH₃)₂), 0.99 (d, J=6.4 Hz, 3H,        CH(CH₃)₂), 1.37-1.48 (m, 4H, —(CH₂)₂—), 2.06-2.15 (m, 1H,        CH(CH₃)₂), 2.54-2.70 (m, 4H, NCH₂—), 3.00 (dd, J₁=5.2 Hz, J₂=7.6        Hz, 1H, NCH), 4.30 (d, J=7.6 Hz, 1H, SHCH), 7.12-7.40 (m, 5H,        ArH)        ¹³C NMR(100 MHz, CDCl₃)    -   δ 18.95 (CH(CH₃)₂), 21.67 (CH(CH₃)₂), 24.46 (—CH₂—), 30.42        (CH(CH₃)₂), 50.60 (NCH₂—), 70.03 (NCH), 77.20 (CHSH), 126.73,        127.9, 128.1, 144.57 (Ph)        Element analysis C₁₅H₂₃NS    -   theoretical: C, 72.23; H, 9.29; N, 5.62    -   experimental: C, 72.01; H, 9.88; N, 5.32        High-resolution MS (70 eV) m/e theoretical: 249.1551    -   experimental: 249.1554        [α]25D=−489.0° (c=1.01, CDCl₃)

EXAMPLE 7 Preparation of(1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-ethanethiol (6g5c) Step (a):Preparing (6g5a)

Repeat Step (a) of EXAMPLE 6, but replace 1,4-dibromobutane with1,5-dibromopentane. Column chromatography (Silica gel, eluent isn-Hexane:EtOAc=10:1) is used to purify the coarse product and aslightly-yellow liquid (1.00 g) is obtained. The yield is 86% and theother analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.80 (d, J=6.8 Hz, 3H, CH(CH ₃)₂), 0.96 (d, J=6.8 Hz, 3H,        CH(CH ₃)₂), 1.62-1.70 (m, 4H, —(CH ₂)₂—), 1.72-1.82 (m, 1H,        CH(CH₃)₂), 2.54 (dd, J₁=4.4 Hz, J₂=8.0 Hz, 1H, NCH), 2.57-2.64        (m, 2H, NCH₂—), 2.68-2.74 (m, 2H, NCH₂—), 4.92 (d, J=4.0 Hz, 1H,        CHOH), 7.14-7.34 (m, 5H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 20.28 (CH(CH₃)₂), 21.81 (CH(CH₃)₂), 23.78 (—CH₂—), 27.88        (CH(CH₃)₂), 51.47 (NCH₂—), 72.29 (NCH), 72.51 (CHOH), 126.08,        126.62, 127.79, 142.88 (Ph)        Element analysis C₁₈H₂₁NO    -   theoretical: C, 77.21; H, 9.93; N, 6.00    -   experimental: C, 77.11; H, 9.73; N, 6.91        High-resolution MS (70 eV) m/e theoretical:233.1780    -   experimental: 234.1865        [α]²⁵ _(D)=−41.3 (c=1.38, CHCl₃)

Step (b): Preparing (1R,2S)-ThioavceticacidS-(3-methyl-1-phenyl-2-pyrrolidin-1-yl-butyl)ester (6g5b)

Repeat Step (b) of EXAMPLE 6, but replace compound (6g4a) with compound(6g5a). Column chromatography (Silica gel, eluent isn-Hexane:NEt₃=100:1) is used to purify the coarse product and aslightly-yellow liquid (1.09 g) is obtained. The yield is 75% and theother analysis includes:

¹H NMR(40 MHz, CDCl₃)

-   -   δ 0.90 (d, J=6.8 Hz, 3H, CH(CH ₃)₂), 0.99 (d, J=6.4 Hz, 3H,        CH(CH ₃)₂), 1.45-1.55 (m, 4H, —(CH ₂)₂—), 1.92-2.04 (m, 1H,        CH(CH₃)₂), 2.26 (s, 3H, SCOCH ₃), 2.60-2.69 (m, 4H, NCH₂—), 2.97        (t, J=6.4 Hz, 1H, NCH), 4.99 (d, J=6.4 Hz, 1H, SCH), 7.14-7.41        (m, 5H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 19.82 (CH(CH₃)₂), 21.62 (CH(CH₃)₂), 24.31 (—CH₂—), 30.57        (CH(CH₃)₂), 30.59 (SCOCH₃), 49.69 (NCH), 50.42 (NCH₂—), 69.33        (CHSCOCH₃), 126.73, 127.86, 128.70, 141.80 (Ph), 194.60 (SCOCH₃)        Element analysis C₂₁H₂₅NOS    -   theoretical: C, 70.06; H, 8.65; N, 4.81; S 11.00    -   experimental: C, 69.68; H, 8.80; N, 4.63; S11.13        High-resolution MS (70 eV) m/e theoretical: 291.1657    -   experimental: 291.1661        [α]²⁵ _(D)=−240.8 (c=1, CHCl₃)

Step (c): Preparing(1R,2S)-3-Methyl-1-phenyl-2-pyrrolidin-1-yl-butane-1-thiol (6g5c)

Repeat Step (c) of EXAMPLE 6, but replace compound (6g4b) with compound(6g5b). A slightly-yellow liquid (0.401 g) is obtained. The yield is85%, and the other analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 0.95 (d, J=7.2 Hz, 3H, CH(CH ₃)₂), 0.99 (d, J=6.4 Hz, 3H,        CH(CH ₃)₂), 1.37-1.48 (m, 4H, —(CH ₂)₂—), 2.06-2.15 (m, 1H,        CH(CH₃)₂), 2.54-2.70 (m, 4H, NCH₂—), 3.00 (dd, J₁=5.2 Hz, J₂=7.6        Hz, 1H, NCH), 4.30 (d, J=7.6 Hz, 1H, SHCH), 7.12-7.40 (m, 5H,        ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 18.95 (CH(CH₃)₂), 21.67 (CH(CH₃)₂), 24.46 (—CH₂—), 30.42        (CH(CH₃)₂), 50.60 (NCH₂—), 70.03 (NCH), 77.20 (CHSH), 126.73,        127.9, 128.1, 144.57 (Ph),        Element analysis C₂₄H₃₃NOS    -   theoretical: C, 72.23; H, 9.29; N, 5.62    -   experimental: C,72.01; H, 9.88; N, 5.32        High-resolution MS (70 eV) m/e theoretical: 249.1551        experimental: 249.1554

[α]²⁵ _(D)=−489.0 (c=1, CHCl₃)

EXAMPLE 8 Preparation of(1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-ethanethiol (7g4c) Step (a):Preparing (1R,2S)-1,2-Diphenyl-2-pyrrolidine-1-yl-ethanol (6g5a)

Repeat Step (a) of EXAMPLE 6, but replace(1R,2S)-2-amino-1-phenyl-3-methyl-butanol with(1R,2S)-2-amino-1,2-diphenyl-ethanol. Column chromatography (Silica gel,eluent is n-Hexane:EtOAc=5:1) is used to purify the coarse product and awhite solid (1.24 g) is obtained. The yield is 93% and the otheranalysis includes:

¹H NMR(400 MHz, CDCl₃)

-   -   δ 1.82-1.85 (m, 4H, N(CH₂CH ₂)₂), 2.59-2.62 (m, 2H, NCH₂),        2.74-2.76 (m, 2H, NCH₂), 3.30 (d, J=3.2 Hz, 1H, NCH), 5.24 (d,        J=3.0 Hz, 1H, CHOH), 6.97-7.25 (m, 10H, ArH)        ¹³C NMR(100 MHz, CDCl₃)    -   δ 23.47 (N(CH₂ CH₂)₂), 52.94 (N(CH₂)₂), 73.99 (NCH), 77.31        (CHOH), 126.08, 126.70, 127.02, 127.19, 127.42, 129.25, 137.47,        140.69 (2Ph)        Element analysis C₁₈H₂₁NO    -   theoretical: C,80.86; H,7.91; N,5.24    -   experimental: C,81.06; H,7.65; N,5.11        High-resolution MS (70 eV) m/e theoretical: 267.3649    -   experimental: 267.3688        [α]²⁵ _(D)=−87.5 (c=1, CHCl₃)        melt point: 113.65±0.45° C.

Step (b): Preparing(1R,2S)-1,2-Diphenyl-2-pyrrolidine-1-yl-1-thioacetyl-ethane (7g4b)

Repeat Step (c) of EXAMPLE 6, but replace compound (6g4b) with compound(7g4a). Column chromatography (Silica gel, eluent isn-Hexane:NEt₃=100:1) is used to purify the coarse product and a yellowliquid (1.33 g) is obtained. The yield is 82% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.74-1.78 (m, 4H, N(CH₂CH ₂)₂), 2.28 (s, 3H, COCH₃), 2.50-2.57        (m, 4H, N(CH₂)₂), 3.48 (d, J=4.8 Hz, 1H, NCH), 5.25 (d, J=5.2        Hz, 1H, SCH), 6.88-7.26 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 23.33 (N(CH₂ CH₂)₂), 30.83 (COCH₃), 52.62 (N(CH₂)₂), 52.85        (NCH), 74.99 (SCH), 126.88, 127.48, 127.59, 128.88, 129.00,        138.64, 140.33 (2Ph), 196.58 (SCOCH₃)        Element analysis C₂₀H₂₃NOS    -   theoretical: C, 73.81; H, 7.12; N, 4.30    -   experimental: C, 73.55; H, 7.26; N, 4.38        High-resolution MS (70 eV) m/e theoretical: 325.4737    -   experimental: 325.4245        [α]²⁵ _(D)=−32.5 (c=1, CHCl₃)

Step (c): Preparing(1R,2S)-1,2-Diphenyl-2-pyrrolidine-1-yl-ethane-1-thiol (7g4c)

Repeat Step (c) of EXAMPLE 6, but replace compound (6g4b) with compound(7g4b). A slightly-yellow liquid (0.43 g) is obtained. The yield is 76%,and the other analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.72-1.79 (m, 4H, N(CH₂CH ₂)₂), 2.29(s, 1H, SH), 2.45-2.51 (m,        2H, NCH₂), 2.55-2.61 (m, 2H, NCH₂), 3.46 (d, J=5.6 Hz, 1H, NCH),        4.70 (d, J=5.2 Hz, 1H, CHSH), 6.96-7.36 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 23.47 (N(CH₂ CH₂)₂), 48.60 (NCH), 52.30(N(CH₂)₂), 75.70        (CHSH), 127.05, 127.09, 127.35, 127.72, 128.63, 129.79, 137.40,        140.85 (2Ph)        Element analysis C₁₈H₂₁NS    -   theoretical: C,76.28; H,7.47; N,4.94    -   experimental: C,76.06; H,7.28; N,5.23        High-resolution MS (70 eV) m/e theoretical: 283.4369    -   experimental: 283.4348        [α]²⁵ _(D)=−162.0 (c=1, CHCl₃)

EXAMPLE 9 Preparation of(1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-ethanethiol (7g5c) Step (a):Preparing (1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-ethanol (7g5a)

Repeat Step (a) of EXAMPLE 6, but replace(1R,2S)-2-amino-1-phenyl-3-methyl-butanol with(1R,2S)-2-amino-1,2-diphenyl-ethanol, and replace 1,4-dibromobutane with1,5-dibromopentane. Column chromatography (Silica gel 50 g, eluent isn-Hexane:EtOAc=5:1) is used to purify the coarse product and a whitesolid (1.28 g) is obtained. The yield is 91% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.45-1.49 (m, 2H, ((CH₂)₂CH₂(CH₂)₂)), 1.55-1.62 (m, 4H,        N(CH₂CH₂)₂), 2.47-2.55 (m, 2H, NCH₂), 2.62 (br, 2H, NCH₂), 3.38        (d, J=4.0 Hz, 1H, NCH), 5.38 (d, J=4.0 Hz, 1H, CHOH), 6.98-7.26        (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 24.60 ((CH₂)₂CH₂(CH₂)₂), 26.28 (N(CH₂CH₂)₂), 52.51 (N(CH₂)₂),        71.55 (NCH), 76.42 (CHOH), 126.14, 126.58, 127.01, 127.42,        129.43, 136.64, 141.38 (2Ph)        IR ν_(max) (cm⁻¹) 3131 (OH)        Element analysis C₁₉H₂₃NO    -   theoretical: C,81.10; H,8.24; N,4.98; O,5.68    -   experimental: C,81.65; H,8.41; N,4.72; O,5.22        High-resolution MS (70 eV) m/e theoretical: 281.1780    -   experimental: 281.1770        [α]²⁵ _(D)=−74.2 (c=1.2, CHCl₃)        melting point: 93-95° C.

Step (b): Preparing(1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-1-thioacetyl-ethane (7g5b)

Repeat Step (b) of Example 6, but the compound (6g4a) is replaced withthe compound (7g5a). Column chromatography (Silica gel 70 g, eluent isn-Hexane:NEt₃=160:1) is used to purify the coarse product and an orangesolid (1.46 g) is obtained. The yield is 86% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.20 (br, 2H, ((CH₂)₂CH₂(CH₂)₂)), 1.26 (br, 2H, NCH₂CH₂), 1.31        (br, 2H, NCH₂CH₂), 2.14 (s, 3H, COCH₃), 2.14 (br, 2H, NCH₂),        2.41 (br, 2H, NCH₂), 3.82 (d, J=10.4 Hz, 1H, NCH), 5.31 (d,        J=10.4 Hz, 1H, SCH), 7.10-7.31 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 24.42 ((CH₂)₂CH₂(CH₂)₂), 26.04 (N(CH₂CH₂)₂), 30.49 (COCH₃),        48.78 (NCH) 50.71 (N(CH₂)₂), 73.28 (SCH), 126.67, 127.32,        127.59, 127.81, 128.25, 128.72, 136.03, 141.72 (2Ph)        Element analysis C₂₁H₂₅NOS    -   theoretical: C,74.29; H,7.42; N,4.13; O,4.71; S9.45    -   experimental: C,74.19; H,7.10; N,4.49; O,4.52; S9.70        high-resolution MS (70 eV) m/e theoretical: 339.5005    -   experimental: 339.5436

Step (c): Preparing (1R,2S)-1,2-Diphenyl-2-piperidin-1-yl-ethanethiol(7g5c)

Repeat Step (c) of EXAMPLE 1, but compound (6g4b) is replaced withcompound (7g5b). A transparent liquid (0.505 g) is obtained. The yieldis 85% and the other analysis includes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.16-1.29 (m, 6H, (CH ₂(CH ₂CH₂)₂N), 2.01 (SH), 2.18(br, 2H,        CH₂(CH₂CH ₂)₂N), 2.34 (br, 2H, CH₂(CH₂CH ₂)₂N), 3.78 (d, J=4.8        Hz, 1H, NCH), 4.68 (d, J=4 Hz, 1H, SCH), 7.14-7.30 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 24.42 ((CH₂)₂ CH₂(CH₂)₂), 26.12 (N(CH₂ CH₂)₂), 44.75(NCH)        50.86 (N(CH₂)₂), 76.36 (SCH), 126.84, 127.32, 127.61, 127.89,        128.03, 129.22, 135.75, 142.03 (2Ph)        Element analysis C₁₈H₂₁NS    -   theoretical: C, 76.72; H, 7.79; N, 4.71; S, 10.78    -   experimental: C, 76.85; H, 7.83; N, 4.75; S, 10.82        High-resolution MS (70 eV) m/e theoretical: 297.1551    -   experimental: 298.0035        [α]²⁵ _(D)=−122.0 (c=1, CHCl₃)

EXAMPLE 10 Preparation of(1R,2S)-1,2-Diphenyl-2-morpholin-4-yl-ethane-1-thiol (7g6c) Step (a):Preparing (1R,2S)-1,2-Diphenyl-2-morpholin-4-yl-ethanol (7g6a)

Repeat Step (a) of EXAMPLE 6, but replace(1R,2S)-2-amino-1-phenyl-3-methyl-butanol with(1R,2S)-2-amino-1,2-diphenylethanol, and replace 1,4-dibromobutane with(BrC₂H₄)₂O. Column chromatography (Silica gel 50 g, eluent isn-Hexane:EtOAc=4:1) is used to purify the coarse product and a whitesolid (1.34 g) is obtained. The yield is 95% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 2.51-2.56 (m, 2H, N(CH₂)₂), 2.66 (br, 2H, N(CH₂)₂), 3.30 (s,        1H, OH), 3.36 (d, J=4.0 Hz, 1H, NCH), 3.70-3.76 (m, 4H,        O(CH₂)₂), 5.33 (d, J=4.0 Hz, 1H, CHOH), 6.94-7.26 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 51.96 (N(CH₂)₂), 67.11 (O(CH₂)₂), 71.18 (NCH), 76.44 (CHOH),        126.11, 126.87, 127.40, 127.56, 127.60, 129.54, 135.56, 140.81        (2Ph)        IR ν_(max) (cm⁻¹) 3127 (OH)        Element analysis C₁₈H₂₁NO₂    -   theoretical: C,76.33; H,7.46; N,4.93; O, 11.28    -   experimental: C,76.38; H,7.36; N,4.90; O,11.36        High-resolution MS (70 eV) m/e theoretical: 283.1573    -   experimental: 283.1570        [α]²⁵ _(D)=−140.7 (c=1.4, CHCl₃)        melting point: 123-125° C.

Step (b): Preparing(1R,2S)-1,2-Diphenyl-2-morpholin-4-yl-1-thioacetyl-ethane (7g6b)

Repeat Step (b) of EXAMPLE 6, but replace compound (6g4a) with compound(7g6a). Column chromatography (Silica gel 70 g, eluent isn-Hexane:NEt₃=100:1) is used to purify the coarse product and an orangesolid (1.57 g) is obtained. The yield is 92% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 2.20 (s, 3H, COCH₃), 2.31-2.35 (m, 2H, N(CH₂)₂), 2.46 (m, 2H,        N(CH₂)₂), 3.51(m, 4H, O(CH₂)₂), 3.72 (d, J=8.8 Hz, 1H, NCH),        5.28 (d, J=8.4 Hz, 1H, SCH), 7.05-7.27 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 30.58(COCH₃), 48.88(NCH), 50.49 (N(CH₂)₂), 66.95(O(CH₂)₂),        73.63(SCH), 126.93, 127.72, 127.78, 127.86, 128.43, 128.94,        135.88, 140.87 (2Ph)        Element analysis C₂₀H₂₃NO₂S    -   theoretical: C,70.35; H,6.79; N,4.10; O,9.37; S9.39    -   experimental: C,70.85; H,6.14; N,4.69; O,6.17; S9.15        High-resolution MS (70 eV) m/e theoretical: 341.4727    -   experimental: 341.4794

Step (c): Preparing (1R,2S)-1,2-Diphenyl-2-morpholin-4-yl-ethane-1-thiol(7g6c)

Repeat Step (c) of EXAMPLE 6, but replace compound (6g4b) with compound(7g6b). Column chromatography (Silica gel 40 g, eluent isn-Hexane:NEt₃=300:1) is used to purify the coarse product and a whitesolid (0.31 g) is obtained. The yield is 53% and the other analysisincludes:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 1.96(s, 1H, SH), 2.39-2.46 (m, 4H, N(CH₂)₂), 3.48-3.56 (m, 4H,        O(CH₂)₂), 3.71 (d, J=8.4 Hz, 1H, NCH), 4.70 (d, J=8.4 Hz, 1H,        CHSH), 7.12-7.30 (m, 10H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 44.75 (NCH), 50.44 (N(CH₂)₂), 66.95 (O(CH₂)₂), 75.87 (CHSH),        127.10, 127.67, 127.94, 128.14, 129.44, 135.10, 141.24 (2Ph)        Element analysis C₁₈H₂₁NOS    -   theoretical: C,72.20; H,7.07; N,4.68; O,5.34; S10.71    -   experimental: C,72.33; H,7.12; N,4.47; O,5.33; S10.75        High-resolution MS (70 eV) m/e theoretical: 299.4359    -   experimental: 299.4358        [Application Mode 1]

To show effect of the aminothiol of the present invention in additionreactions of organic zinc and aldehyde, diethylzinc (ZnEt₂) andbenzaldehyde are provided to perform the following reaction:

Table 2 lists chiral ligands and conditions applied in the additionreaction. In the application, the chiral ligand obtained in the aboveEXAMPLEs is added into a dried flask at an equivalence concentration(N_(lig)). The flask is then sealed and vacuumed to remove moisture andthen filled with nitrogen. Diethylzinc (ZnEt₂) dissolved in toluene orhexane is added in the flask at an equivalence concentration (N_(ZE))and a proper temperature. Next, under a specific temperature (T_(rxn)),benzaldehyde (0.11 mL, 1.0 mmol) is added into the flask and stirred fora period (t_(rxn)). To terminate the reaction, 1N aqueous HCl (1 mL) isadded into the above solution. The solution is then extracted withacetyl acetate (20 mL), wherein the organic layer is collected anddehydrated with anhydrous MgSO₄, and then the mixture is filtered. Thefiltrate is concentrated by reducing pressure through an air pump toobtain crude product. The crude product is purified by columnchromatography (Silica gel, eluent is n-Hexane: EtOAc=10:1).

HPLC (high-pressure liquid chromatography) with Daicel Chiralcel ODColumn is provided for determining enantiomeric excess (e.e.) of theproduct, wherein the eluent is n-hexane:i-propanol=98.0:2.0, flow rateis 1.5 ml/min. In the above addition reaction of ZnEt₂ and variousaldehyde, peaks of products are present at different time, as indicatedin Table 3. The enantiomeric excess (e.e.) can be determined accordingto the following equation:

${e.e.\;(\%)} = {\frac{{S - R}}{S + R} \times 100\;\%}$wherein (S+R) in denominator is the product obtained without addingchiral ligands of the present invention;

-   -   S or R in numerator is the product obtained by adding chiral        ligands of the present invention.

TABLE 2 N_(lig) N_(ZE) t_(rxn) T_(rxn) e.e. EXAMPLE Ligand (meq) S/C(meq) Solvent (h) (° C.) (%) 1 6b4c 0.05 20 1.2 Toluene 12 −20 96.5 R 22f4c 0.05 20 1.2 Toluene 12 −20 95.7 R 3 6c4c 0.05 20 1.2 Toluene 12 −2094.2 R 4 3f4c 0.05 20 1.2 Toluene 12 −20 93.2 R 5 6f4c 0.05 20 1.2Toluene 12 −20 99.6 R 0.05 20 1.2 Toluene 6 rt 98.5 R 0.05 20 1.2Toluene 12 0 99.3 R 0.05 20 1.2 Toluene 12 −20 99.6 R 0.05 20 1.2 Hexane12 −20 99.2 R 0.05 20 1.2 T/THF 12 −20 92.1 R 0.05 20 1.2 T/CH2Cl2 12−20 99.5 R 0.05 20 1.2 T/C6H6 12 −20 99.6 R 0.05 20 2 Toluene 12 −2099.6 R 0.05 20 3 Toluene 12 −20 99.5 R 0.05 20 4 Toluene 12 −20 99.5 R0.05 20 5 Toluene 12 −20 99.5 R 0.05 20 1.2 Toluene 12 −40 99.7 R 0.0520 1.2 Toluene 24 −78 90.2 R 5 6f4c 0.5 2 1.2 Toluene 12 −20 99.6 R 0.25 1.2 Toluene 12 −20 99.6 R 0.05 20 1.2 Toluene 12 −20 99.6 R 0.001 10001.2 Toluene 12 −20 99.2 R 0.0005 2000 1.2 Toluene 12 −20 98.5 R 0.000110000 1.2 Toluene 12 −20 96.5 R 6 6g4c 0.05 20 1.2 Toluene 6 rt 98.3 R0.05 20 1.2 Toluene 12 0 99.3 R 0.05 20 1.2 Toluene 12 −20 99.5 R 0.0520 1.2 Toluene 12 −40 99.6 R 0.05 20 1.2 Toluene 24 −78 88.2 R 7 6g5c0.05 20 1.2 Toluene 12 rt 99.0 R 0.05 20 1.2 Toluene 12 0 99.0 R 0.05 201.2 Toluene 12 −20 99.6 R 0.01 100 1.2 Toluene 12 −20 99.0 R 0.001 10001.2 Toluene 12 −20 98.1 R 0.05 20 1.2 Toluene 12 −40 99.6 R 0.05 20 1.2Toluene 12 −78 93.7 R 8 7g4c 0.1 10 5 Toluene 12 −20 99.3 R 0.1 10 4Toluene 12 −20 99.5 R 0.1 10 3.7 Toluene 12 −20 99.5 R 0.1 10 3 Toluene12 −20 99.4 R 0.1 10 2 Toluene 12 −20 99.3 R 0.1 10 1.2 Toluene 12 −2099.3 R 0.05 20 1.2 Toluene 6 rt 99.1 R 0.05 20 1.2 Toluene 9 0 99.2 R0.05 20 1.2 Toluene 12 −20 99.3 R 0.05 20 1.2 Toluene 12 −40 99.5 R 0.0520 1.2 Toluene 24 −78 94.2 R 0.0002 5000 3.7 Toluene 12 −20 99.0 R0.0005 2000 3.7 Toluene 12 −20 99.1 R 0.001 1000 3.7 Toluene 12 −20 99.2R 8 7g4c 0.003 333 3.7 Toluene 12 −20 99.3 R 0.006 167 3.7 Toluene 12−20 99.3 R 0.01 100 3.7 Toluene 12 −20 99.3 R 0.02 50 3.7 Toluene 12 −2099.4 R 0.05 20 3.7 Toluene 12 −20 99.4 R 0.1 10 3.7 Toluene 12 −20 99.5R 0.2 5 3.7 Toluene 12 −20 99.5 R 0.4 3 3.7 Toluene 12 −20 98.8 R 9 7g5c0.1 10 3.7 Toluene 12 −20 99.7 R 0.05 20 2 Toluene 12 0 99.7 R 10 7g6c0.1 10 3.7 Toluene 12 −20 99.5 R

In Table 2, S/C is an equivalence ratio of benzaldehyde (substrate, 1.0mmol) to the chiral ligand. As shown in Table 2, the chiral ligands ofthe present invention exhibit superior enantioselectivity in theasymmetric of benzaldehyde and diethyl zinc, even as S/C are very high.For example, when compounds (6f4c), (6g5c) and (7g4c) obtained fromEXAMPLEs 5, 7 and 8 are applied at S/C as high as 1,000, enantiomericexcess are more than 98%. Therefore, aminothiol compounds in the presentinvention are indeed very economic for applying the above asymmetricreactions to industries.

Table 3 list more aminothiol compounds with various ligands andapplication results thereof in varied reaction conditions. Theseaminothiol compounds can be produced through similar procedures of aboveEXAMPLEs by supplying proper reactants having respective ligands.Therefore, detailed description is omitted in the specification.

In Table 3, Compound (5g3c) has the following formula.

The related analysis of Compound (5g3c) include:

¹H NMR (400 MHz, CDCl₃)

-   -   δ 3.04-3.22(m, 2H, PhCH₂), 3.503.60 (m, 1H, CNH), 3.60 (s, 4H,        PhCH₂N), 4.37 (t, J=4.0 Hz, 1H, PhCHS), 6.81-7.41 (m, 20H, ArH)        ¹³C NMR (100 MHz, CDCl₃)    -   δ 24.68, 26.53, 46.06, 51.41, 72.86, 125.83, 126.81, 127.94,        128.10, 128.14, 129.31, 140.85, 143.663.        Element analysis C₂₉H₂₉NS

TABLE 3 N_(lig) N_(ZE) t_(rxn) T_(rxn) e.e. Ligand (meq) S/C (meq)Solvent (h) (° C.) (%) 2g5c 0.05 20 2 Hexane 12 0 100.0 R 0.05 20 1.2Toluene 12 rt 91.0 R 0.05 20 1.2 Toluene 12 0 97.9 R 4g5c 0.0005 20001.2 Toluene 12 −20 97.7 R 0.0001 10000 1.2 Toluene 12 −20 98.1 R 0.005200 1.2 Toluene 12 −20 98.1 R 0.001 1000 1.2 Toluene 12 −20 98.1 R 0.0520 1.2 Toluene 12 −20 98.9 R 0.1 10 1.2 Toluene 12 −20 98.9 R 0.2 5 1.2Toluene 12 −20 98.8 R 0.05 20 1.2 Toluene 12 −40 99.3 R 5g2c 0.05 20 1.2Toluene 12 rt 96.9 R 5g3c 0.05 20 1.2 Toluene 12 0 93.5 R 5g4c 0.05 201.2 Toluene 12 0 98.9 R 5g5c 0.05 20 5 Toluene 12 0 99.1 R 0.05 20 4Toluene 12 0 99.4 R 0.05 20 3 Toluene 12 0 99.4 R 0.05 20 2 Toluene 12 099.3 R 0.05 20 1.2 Toluene 12 0 99.3 R 0.05 20 1.1 Toluene 12 0 99.3 R0.05 20 1.2 Hexane 12 0 99.1 R 0.05 20 1.2 T/CH2Cl2 12 0 99.1 R 0.05 201.2 T/THF 12 0 72.0 R 0.0001 10000 1.2 Toluene 12 0 98.1 R 0.0002 50001.2 Toluene 12 0 98.9 R 5g5c 0.0005 2000 1.2 Toluene 12 0 99.0 R 0.0011000 1.2 Toluene 12 0 99.1 R 0.002 500 1.2 Toluene 12 0 99.1 R 0.005 2001.2 Toluene 12 0 99.2 R 0.01 100 1.2 Toluene 12 0 99.3 R 0.02 50 1.2Toluene 12 0 99.3 R 0.05 20 1.2 Toluene 12 0 99.3 R 0.1 10 1.2 Toluene12 0 99.4 R 0.2 5 1.2 Toluene 12 0 99.4 R 0.5 2 1.2 Toluene 12 0 99.4 R1 1 1.2 Toluene 12 0 99.0 R 0.05 20 1.2 Toluene 3 rt 98.1 R 0.05 20 1.2Toluene 12 0 99.3 R 0.05 20 1.2 Toluene 18 −20 99.4 R 0.05 20 1.2Toluene 24 −40 99.4 R 0.05 20 1.2 Toluene 48 −78 87.9 R 0.05 20 1.2Toluene 0.5 rt 97.8 R 0.05 20 1.2 Toluene 1 rt 98.1 R 0.05 20 1.2Toluene 1.5 rt 98.1 R 5g5c 0.05 20 1.2 Toluene 3 rt 98.1 R 0.05 20 1.2Toluene 6 rt 98.1 R 5g6c 0.05 20 1.2 Toluene 12 0 98.2 R 6g1c 0.05 201.2 Toluene 12 −20 97.7 R 6g2c 0.05 20 1.2 Toluene 12 −20 99.4 R 6g6c0.05 20 1.2 Toluene 12 0 99.1 R 0.05 20 1.2 Toluene 12 −20 99.4 R

As shown in Table 3, the aminothiol compounds of the present inventionindeed perform excellent catalysts to obtain high enantiomeric excess inthe asymmetric addition reaction of benzaldehyde and diethyl zinc.

Similarly, the aminothiol compounds of the present invention can beprovided as chiral ligands to react with other organic metals, forexample, Cu, to form organometal complexes. These complexes can alsoreact with carbonyl such as aldehyde, to produce alcohol in theasymmetric addition reactions.

[Application Mode 2]

The aminothiol compounds of the present invention also show superioreffect in catalizing an addition reaction as follows:

In this reaction, butyl acetylene (or hexyl acetylene), diethylzinc(ZnEt₂) and aldehyde are reacted to produce allyl alcohol in existenceof chiral ligands of the present invention. Table 4 lists conditions andresults of the reaction catalized with different ligands includingCompound (6g5c) obtained in Example 7, Compound (7g5c) obtained inExample 9, Compound (7g6c) obtained in Example 10 and Compound (6f5c).

TABLE 4 Conver- Mole % T_(rxn) N_(ZE) t_(rxn) sion Yield e.e Ligand ArR′ of ligand (° C.) (eq) (h) (%) (%) (%) 6f5c Ph C₄H₉ 5(T) −10 2 15 10089 91.3(R) Ph C₄H₉ 5(T) −20 2 15 100 94 99.0(R) Ph C₄H₉ 5(T) −20 2 15100 94 98.3(R) Ph C₄H₉ 1(T) −30 2 15 100 90 94.3(R) Ph C₄H₉ 2(T) −30 215 100 92 94.5(R) Ph C₄H₉ 5(T) −30 2 15 100 94 98.2(R) Ph C₆H₁₃ 2(T) −302 15 100 65 99.0(R) 4-OMe—Ph C₆H₁₃ 2(T) −30 2 15 100 90 98.1(R) 2-Cl—PhC₆H₁₃ 2(T) −30 2 15 100 86 92.6(R) Ph C₆H₁₃  2(H)  −30 2 15 100 8099.0(R) Ph C₄H₉ 5(T) −30 2 15 100 94 98.2(R) 2-Cl—Ph C₄H₉ 5(T) −30 2 15100 — 98.1(R) Ph C₆H₁₃ 5(T) −30 2 15 100 — 99.4(R) Ph C₄H₉ 5(T) −40 2 15100 94 98.3(R) Ph C₄H₉ 15(T)  −30 2 15 100 — 99.5(R) 6g5c Ph C₄H₉ 5(T)−30 2 15 100 92 96.1(R) Ph C₆H₁₃ 2(T) −30 2 15 100 92 98.6(R) 7g5c PhC₄H₉ 5(T) −30 2 15 100 91 95.6(S) Ph C₄H₉ 5(T) −30 2 15 100 93 97.0(R)Ph C₆H₁₃ 2(T) −30 2 15 100 93 98.4(R) Ph C₆H₁₃ 5(T) −30 2 15 100 6898.3(R) 7g6c Ph C₄H₉ 5(T) −30 2 15 100 95 97.3(R)

In Application Mode 2, ZnEt₂ and aldehyde are respectively added bysyringe pump over 20 minutes. T and H in the column (mole % of ligand)are the solvents toluene and hexane. Detailed procedures may be referredto Wolfgang Oppolzer et al. (J. Org. Chem. 2001, 66, 4766-4770) andBrase S. et al. (Org. Lett. 2001, 3, 4119). Enantiometric access isdetermined with HPLC (Chiralcel OD-H column, flow rate 0.7 ml/min, 3%isopropanol).

It should be noticed that the above embodiments are only used forexplaining the present invention, but not limiting the scope.

1. An aminothiol compound, having a structural formula selected from thegroup consisting of:


2. The aminothiol compound as claimed in claim 1, which is used forcatalyzing an asymmetric addition reaction of an organic metal compoundand aldehyde.
 3. The aminothiol compound as claimed in claim 2, whereinsaid organic metal is Zn or Cu.